1. Field of the Invention
The present invention relates generally to pharmaceutical compositions, methods and implants, and more specifically, to compositions, implants, and methods for treating diverticular disease (e.g., diverticulitis).
2. Description of the Related Art
Diverticular disease is a condition whereby there is herniation of the mucosa and submucosa of a hollow organ, such as the gastrointestinal (GI) tract, urinary tract, or repiratory tract, which produces outpouchings through the muscular wall of the body passageway. Although diverticula can occur in any tubular organ, diverticular disease is of greatest clinical relevance in the lower GI tract (large bowel or colon), where it can cause life threatening inflammation and infection (diverticulitis) or bleeding (lower GI hemorrhage). Typically this condition is treated medically or through open surgical removal of the diverticula and/or complete resection of the segment of the bowel that contains them.
Diverticular disease (which encompasses diseases such as diverticulosis and diverticulitis) is an important medical condition and is the most common cause of large bleeds in the colon, accounting for 30% to 50% of massive GI hemorrhage. Diverticular disease results when a small pouch (referred to as a diverticulum) in the colon bulges outward through weak spot. About 10% of Americans over the age 40 have diverticulosis (i.e., the condition of having diverticula), and the condition becomes more common as people age (33% of the population over the age of 60 and 50% of people over 80 have diverticular disease). In many patients, diverticulosis remains asymptomatic. However, in about 10–25% of people with diverticulosis, the pouches become infected or inflamed. This condition, referred to as diverticulitis, can cause abdominal pain (in particular around the left side of the lower abdomen), peritonitis, abscess formation, and lower GI bleeding. Perhaps the most serious consequence of diverticular disease is lower intestinal hemorrhage (blood passed via the rectum). As many as 15% to 40% of diverticulosis patients experience an episode of bleeding, and 25% of those patients will have a recurrent bleeding episode. After a second hemorrhage, the chance of a third bleed is approximately 50%. The combined mortality and significant morbidity rate associated with diverticular hemorrhage is 10% to 20%, in part due to patient age and comorbidity with other conditions such as cardiac, pulmonary, or renal dysfunction.
Generally, diverticular bleeds are massive, painless, and self limiting. In 5% of diverticular patients, however, the bleed is substantial enough to cause cardiovascular instablility and may require transfusion. Treatment of diverticular disease generally involves resuscitation, which includes large bore intravenous access, placement of a foley catheter, placement of a nasogastric tube to rule out upper gastrointestinal bleed, and administration of intravenous fluids. Patients are most frequently treated supportively with volume resuscitation, correction of coagulation abnormatlities and blood transfusion, if required. Most active lower GI bleeds will stop spontaneously. However, 18% to 25% of patients with diverticular bleed will become hemodynamically unstable as a result of the hemorrhage and continue to be unstable despite aggressive resuscitation. In cases of massive or severe bleeding, urgent surgery (e.g., segmented colectomy, blind segment resection, abdominal colectomy, total abdominal colectomy, and subtotal colectomy) may be required to attempt to stop the bleeding.
Although several pharmacological approaches for treating diverticulitis are described (see, e.g., U.S. Pat. Nos. 4,837,229; 6,297,214; 6,114,304; and 4,455,305), none have proven to be particularly effective. For example, hemodynamically stable, actively bleeding patients can be treated with vasospastic substances such as vasopressin. Risks associated with vasospastic substances include a re-bleed rate of 50% in patients after withdrawl of the medication, decreased coronary perfusion, hypertension, and cardiac arrythmias. Alternately, embolization (clogging the arteries that supply the bleeding bowel segment with small, locally injected particles) can sometimes stop the bleeding but is associated with colon infarctions and is preferably reserved only for patients who present a poor surgical risk.
Currently no reliable way exists to acutely treat diverticulitis, other than supportive measures, or urgent surgery in severe cases. Even for patients in whom symptoms spontaneously resolve (i.e., bleeding ceases), currently no reliable nonsurgical interventions can be employed to prevent recurrent bleeding. Also, many patients who would benefit from surgical resection of their diverticula are often not surgical candidates because of age, frailty as a result of blood loss, or other concurrent medical conditions. Therefore, a significant unmet medical need remains to develop nonsurgical, minimally invasive interventions that can eliminate diverticula and the morbidity and mortality associated with them.